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SEMINAR ON CHIRALITY (PREFORMULATION ASPECTS)

SEMINAR ON CHIRALITY (PREFORMULATION ASPECTS). 1 / 33. CONTENTS. 1. INTRODUCTION 2 . TERMS 3 . NOMENCLATURE OF CHIRAL COMPOUNDS 4 . IMPORTANT OF CHIRALITY 5 . SPECIFIC REQUIREMENTS FOR CHIRAL CRUG DEVELOPMENT 6 . APPLICATION OF CHIRALITY IN FORMULATION AND DEVELOPMENT

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SEMINAR ON CHIRALITY (PREFORMULATION ASPECTS)

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  1. SEMINAR ONCHIRALITY(PREFORMULATION ASPECTS) 1 / 33

  2. CONTENTS 1.INTRODUCTION 2. TERMS 3. NOMENCLATURE OF CHIRAL COMPOUNDS 4. IMPORTANT OF CHIRALITY 5. SPECIFIC REQUIREMENTS FOR CHIRAL CRUG DEVELOPMENT 6. APPLICATION OF CHIRALITY IN FORMULATION AND DEVELOPMENT 7. CHIRAL RESOLUTION 2 / 33

  3. Chiral drug contain chiral atom More than 50% drugs are chiral Opposite enantiomer of chiral drug often differs in pharmacodynamic, pharmacokinetic and toxicological properties. “Racemic switch” 1. INTRODUCTIOIN 3 / 33

  4. 4/33

  5. 2.TERMS • CHIRAL :Molecules that are not super imposable on their mirror images. • CHIRAL CARBON isto which four different groups are attached. e.g, LACTIC ACID 5 / 33

  6. 2-METHYL-1-BUTANOL 6 / 33 • Stereoisomer • The particular types of isomer that differ from each other only in the way the atoms are oriented in space are called as STEREOISOMERS.

  7. Ephedrine (-) Ephedrine (+) 7 / 33 • Enantiomer • Isomers which are mirror images to each other and yet are not superimposable are called an EANANTIOMER.

  8. 8 /33 Diasteriomer Meso compound Racemic mixture Eutomer Distomer Eudismic index Racemization Chiral inversion

  9. 3. NOMENCLATURE OF CHIRAL COMPOUNDS  OPTICAL ISOMERS: clockwise then dextro (+) anticlockwise then levo (-)  CIRCULAR DICHROISM: Differential absorption of left and right circularly polaried rotation. There are differences in absorption of the left and right handed components of circularly polarised light by a non racemic sample. 9 / 33

  10. GEOMETRIC ISOMERS: same side then cis (Z) • opposite side then trans (E) • H HH CH3 • C=C (CIS) C=C (TRANS) • CH3 CH3CH3 H • CONFIGURATIONAL ISOMER: • clockwise then R • anticlockwise then S 10/33

  11. 4. IMPORTANT OF CHIRALITY 4.1STERIC ASPECTS OF PHARMACOKINETICS 4.2 STERIC ASPECTS OF PHARMACODYNEMICS 4.3 CHIRAL IMPURITIES 4.4 ADVANTAGES OF SINGLE ENANTIOMER AS A DRUG 11 / 33

  12. 4.1 STERIC ASPECTS OF PHARMACOKINETICS 4.1.1 DRUG ABSORPTION • same absorption rate for passive diffusion for enantiomer • sterioselective absorption for carrier mediated absorption • Stereoisomers with structural similarities to endogenous entities and nutrients display difference in permeability rates across the g.i. membrane and hence in bioavailability. 12/33

  13. L-DOPA absorbed by an amino acid transport system is passes 4 to 5 times greater then that of D- ENANTIOMER. • Bioavailability of D-METHOTREXATE appears markedly lower then L-ISOMER. • The L-METHOTREXATE is absorbed by activeprocesses and the D-METHOTREXATE is by passive absorption. • Crystalline structure of racemates may not same as individual sterioisomers and there may be difference in dissolution rate of racemate and single enantiomer. 13/33

  14. 4.1.2 DRUG DISTRIBUTION • The interaction of enantiomer with a plasma protein yields a diastereomeric association. • (+)Oxazepamhemisuccinatehas 30 to 50 time higher association constants for albumin than its (-) isomer. • The S isomer of warfarin is bound to a greater extent to albumin than R isomer. • Human albumin binds R-propranolol more strongly than S-form. 14/33

  15. 4.1.3 DRUG BIOTRANSFORMATION • The intrinsic hepatic clearance of S-warfarin is reported to be approximately two fold greater than that of R-warfarin. CHIRAL INVERSION *S(+) IBUPROFENR(-) IBUPROFEN ANTI-INFLAMATORY ACTIVITY NO ANTI-INFLAMATORY ACTIVITY (*Ref: C.A:147(2) JULY; 2OO7;3868a) 15/33

  16. 4.1.4 DRUG ELIMINATION • The renal clearance of S-prenylamineis approximately 2.4 times higher than that of the R isomer. d-PROPOXYPHENE l-PROPOXYPHENE ANALGESIC ACTIVITY NO ACTIVITY BUT INHIBITS RENAL CLEARANCE OF d-ISOMER RACEMIC 16/33

  17. 4.2 STERIC ASPECTS OF DRUG ACTION 17/33

  18. 4.3 CHIRAL IMPURITY . 18/33

  19. The presence of small amounts of opposite enantiomer may significantly reduce the apparent solubility of the enantiomer, because the racemic compound will form in the solution and may precipitate from the solution. • For example, the solubility of (+) dexclamol hydrochloride is five times that of (_) dexclamol hydrochloride. • In ephedrine and pseudoephedrine studies demonstrated that traces of the enantiomeric impurity might cause significant changes in the physicochemical properties of the pure enantiomer. 19/33

  20. 4.4 ADVANTAGES OF USE OF SINGLE ENANTIOMER AS A DRUG • Separating unwanted pharmacodynamic side effects • Reduce metabolic/renal/hepatic drug load. • Reduce drug interactions. • Avoid bioinversion • Easier assessment of physiology, disease, and drug co-administration effects. 20/33

  21. 5. SPECIFIC REQUIREMENTS FOR CHIRAL DRUG DEVELOPMENT • Development of enantiomeric assay. • Synthesis of individual enantiomer. • Safety evaluation of the individual enantiomer. • Pharmacokinetic of individual enantiomers. • Resolution of the individual enantiomer. • Chiral conversion 21/33

  22. 6. APPLICATION OF CHIRALITY IN F AND D ECONOMICAL CONSIDERATION 22/33

  23. 6.1 ACCEPTANCE AND REJECTION OF API • The Chiraly pure drugs should be quantitatively analyzed for the presence or absence of chiral impurities besides the routine determination of related impurities. • The quantitative chiral analysis could be done by TANDEMMS. • Accept or reject a sample of API is based on the ratio of the active/inactive enantiomers in the non-racemic mixtures. • The intrinsic dissolution rate of chiraly pure API may prove to be a useful QUALITY CONTROL PARAMETER. 23/33

  24. 6.2 SELECTION OF ADJUVANTS • The adjuvant may be • chiral or • non-chiral • The type and amount of the adjuvant may determine the functionality of the dosage form, especially the drug release rate. • The release of salbutamol and ketoprofen enantiomers from hydroxypopylmethylcellulose (HPMC) matrixes shows that stereoselectivity is dependent on the amount of chiral excipient in the formulation 24/33

  25. The release of eutomer R-salbutamol was higher than that of the distomer S-salbutamol from the gamma cyclodextrin tablets. • So by selecting proper chiral excipient, distomer can be retained in the dosage form. • Applications of interaction between API and chiral excipient may be explored in the areas of sustained release buccal dosage form and colon drug delivery system. • Drug delivery system containing D-pantothanic acid entrapped in pillared hydrotalcite* ( * CA Sep.10,2007.no.11 vol.147) 25/33

  26. 6.3 IN VITRO DISSOLUTION STUDIES AND VIVO STUDY • Crystals of both enantiomer & racemic compound are having different molecular arrangement. • Due to the difference between the crystal lattice of both forms, the solubility of pure enantiomers may be different from the racemic compound. • The initial dissolution rate of racemic PROPRANOLOL HCL was three times greater than that of enantiomers in distilled water. 26/33

  27. 6.4 STABILITY STUDY • Racemization, or an optically inactive mixture of corresponding dextro (d-) and levo forms is a major factor in PHARMACEUTICAL STABILITY. • Thalidomide undergoes chemical racemization in aqueous media. • Besides chemical stability, dissolution stability is also important for tablets and capsules. 27/33

  28. 6.5 NDA/ANDA APPLICATION • We should also keep in mind that increasing the desired activity should not accompanied by a rise in the untoward effect. • FDA requires toxicology testing on the racemate. • The data of stereoselective dissolution testing should be submitted for the enantiomers that exhibit different action. 28/33

  29. 7. CHIRAL RESOLUTION • Separation of racemic mixture in to the individual enantiomer. • Methods use are : • crystallization method • chemical method • biochemical method • electrophoresis • chromatography 29/33

  30. List of official chiral drugs: 30/33

  31. REFERENCES • Williams Lemke.Foye’s principle of medicinal chemistry. Ed.5. p=49-54 • Morrison Boyd. Organic chemistry. Ed.6. p=133 • ‘‘Relationship between physical properties and crystal structures of chiral drug’’Z.jane Li and David J.W.Grant. October 1997, Volume-86,Number 10 • Encyclopedia of pharmaceutical technology. Volume-8. p=281. • A.J.Romero and C.T.Rhodes, Chirality, 3, 1 (1991) 31/33

  32. Continue… 6. ‘‘Overview on Chirality and Application of Stero-selective Dissolution testing in the Formulation and Development work’’ by MukeshC.Gohel. www.dissolutiontech.com • www.harrisononline.com • Indian pharmacopoeia 1996 • British pharmacopoeia 1993 • United state pharmacopoeia 2000 32/33

  33. THANK YOU 33/33

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